CAB59:HIVandneurocogni5veimpairment

Friday8thJuly2016

HIVNeurology

ConsultantNeurologist,Chelsea&WestminsterHospital&ImperialCollegeNHSTrust(CharingCrossHospital),London

Dr Nick Davies

Aimsoftalk

•  Pre-ARTNeurology

•  Post-ART•  IRIS•  Cogni<veImpairment:HAND;drugtoxicity

•  Majoromissions•  PeripheralNeuropathy•  Stroke(MylesConnor)

Introduc<on

•  WhatistheHumanImmunodeficiencyVirus?•  Retrovirus(ssRNA);possessesreversetranscriptase•  Infects:

•  CD4Thelpercells•  Macrophages•  Dendri<ccells•  Microglia

•  Lymphotropic&Neurotropic•  M-tropic(CCR5);T-tropic(CXCR4)•  HIV-1&HIV-2•  HIV-1clades(AtoE)–BcommonestUS&Europe

NeurologicalComplica<onsofImmunosuppression

Davies, N. & Thwaites, G. Infections of the nervous system. Pract Neurol 11, 121-131 (2011).

An<-retroviralTherapy

Source: Yin et al. HIV in the UK 2014 Report: data to end of 2013. Nov 2014; PHE, London

Sites of Action of Current Antiretroviral Drug Classes

Source of image: http://en.wikipedia.org/wiki/File:HIV-drug-classes.svg

ImmuneRecons<tu<onInflammatorySyndrome(IRIS)

Johnson, T. & Nath, A. Neurological complications of immune reconstitution in HIV-infected populations. Ann N Y Acad Sci 1184, 106-120 (2010).

•  Definition: “a paradoxical deterioration in clinical status attributable

to the recovery of the immune system during HAART.”

1 Johnson, T. & Nath, A. Neurological complications of immune reconstitution in HIV-infected populations. Ann N Y Acad Sci 1184, 106-120 (2010).

IRIS:Classifica<on1

Johnson, T. & Nath, A. Neurological complications of immune reconstitution in HIV-infected populations. Ann N Y Acad Sci 1184, 106-120 (2010).

IRIS:Classifica<on1

Simultaneous = Unmasked Delayed = Paradoxical

14/8/15 04/9/15

14/8/15 04/9/15 06/10/15

IRIS:Classifica<on1

1Johnson, T. & Nath, A. Neurological complications of immune reconstitution in HIV-infected populations. Ann N Y Acad Sci 1184, 106-120 (2010). 2 Miller, R.F., Isaacson, P.G., Hall-Craggs, M., et al. Cerebral CD8+ lymphocytosis in HIV-1 infected patients with immune restoration induced by HAART. Acta Neuropathol 108, 17-23 (2004).

CD8 Encephalitis2

Autoimmune Conditions: •  GBS •  SLE •  Grave’s disease

Without HIVE

With HIVE

HIVCogni<veImpairmentpre-cART

Navia et al (Price) The AIDS Dementia Complex Annals of Neurology 19: 517-524 McArthur, J.C., Brew, B.J. & Nath, A. Neurological complications of HIV infection. Lancet Neurol. 4, 543-555 (2005).

Manji (2013) HIV, Dementia, & ARVs: 30 years of an epidemic JNNP 84: 1126-37

•  HIVdemen<a;HIVencephalopathy;AIDSdemen<acomplex•  Life<meprevalence15%•  30%terminalAIDS•  Subcor<caldemen<a–triad:

•  CogniHon;•  MotorfuncHon;•  Behaviour

HIVCogni<veImpairment:ArrivalofART•  HIVDemen<anowonlyseenbecause:

– Burnt-out–damagesustainedpriortoART– LatepresentaHon– Non-adherencetoARVs– Rarelyinpa<entswhereCNS&systemicinfec<onfollownon-parallelcourses

•  Long-termnon-progressors•  OnART;differentresistancepa`erns “Compartmentphenomenon”

“SymptomaHcCSFescape”»  Canbefulminantwithseizures

Schouten, J., Cinque, P., Gisslen, M., Reiss, P. & Portegies, P. HIV-1 infection and cognitive impairment in the cART era: a review. AIDS 25, 561-575 (2011).

HIVCogni<veImpairment:cART-era

•  Pa<entswithsystemiccontrolofHIVandhighCD4cellcountscomplainingof:– Mildmemoryproblems– Slowness– DifficulHesinconcentraHon– DifficulHesinplanning– DifficulHesinmulHtasking

•  Pa<entswithneurodegenera<vedisease–  ARVs

Schouten, J., Cinque, P., Gisslen, M., Reiss, P. & Portegies, P. HIV-1 infection and cognitive impairment in the cART era: a review. AIDS 25, 561-575 (2011).

Anewterminology:HAND

1Antinori, A., et al. Updated research nosology for HIV-associated neurocognitive disorders. Neurology 69, 1789-1799 (2007). 2Gisslen, M., Price, R.W. & Nilsson, S. The definition of HIV-associated neurocognitive disorders: are we overestimating the real prevalence? BMC Infect Dis 11, 356 (2011).

Frascati Criteria1

Nb If criterion has Normal distribution 2.3% fall >2SD; 15.9% >1 SD2

HIVCogni<veImpairment:ART-era•  CHARTERstudy(CNSHIVARVTherapyEffectsResearch)

•  52%Cogni<veimpairment(n=1555)–  33%Asymptoma<cNeurocogImpairment–  12%MildNeurocogDisorder–  2%HAD

•  HigherincidenceCIinthosewithmorecomorbi<es

–  40%;59%;83%

Heaton, R.K., et al. HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study. Neurology 75, 2087-2096 (2010).

HIVCogni<veImpairment:cART-era•  Whataboutconfounds?1

–  Currentdruguse–  Hepa<<sCco-infec<on–  Depression–  “Burntout”CNSdisease

•  HANDincidence–  Virologicallysuppressed:18%–  Non-virologicallysuppressed:24%

•  UKstudyinsuppressedasymptoma<c:19%2

1Cysique, L.A. & Brew, B.J. Prevalence of non-confounded HIV-associated neurocognitive impairment in the context of plasma HIV RNA suppression. J Neurovirol 17, 176-183 (2011). 2Garvey, L., Surendrakumar, V. & Winston, A. Low Rates of Neurocognitive Impairment Are Observed in Neuro-Asymptomatic HIV-Infected Subjects on Effective Antiretroviral Therapy. HIV Clin Trials 12, 333-338 (2011).

STUDIES TYPICALLY CROSSECTIONAL NOT LONGITUDINAL

SummaryofRevised(2010)CNSPenetra<on-Effec<veness(CPE)RankingofARVs

4 3 2 1 NRTIs AZT ABC ddI TDF

FTC 3TC dDI

d4T NNRTIs NVP DLV ETV

EVF PIs

IDV/r DRV/r ATV/r NFV

FPV/r ATV RTV IDV FPV SQV/r

LPV/r SQV

Fusion/Entry Inhibitors

MVC

Integrase inhibitors

RAL ENF

Letendre, S et al. 17th CROI 2010. Abstract 430.

HIVCogni<veImpairment:cART-era•  CPEEvidence:

–  Smurzynskietal•  Cross-sec<onalstudy;VL<50•  HigherCPEscoreinthoseon>3ARVsbe`erthanlowerCPEscore

–  Marraetal•  DichotomisedCPE(old)>2or<2•  HigherCPEassociatedwithgreaterCSFsuppression

•  ThosewithimpairedneuropsychatentrydidworsewithhigherCPE

1Smurzynski et al Effects of CNS ARV penetration of cognitive in ALLRT AIDS 2011; 25: 357-365 2Marra, C.M., et al. Impact of combination antiretroviral therapy on cerebrospinal fluid HIV RNA and neurocognitive performance. AIDS 23, 1359-1366 (2009)

HIVCogni<veImpairment:cART-era

•  ProblemswithCPE:•  Categorical not ordinal •  Methodology not transparent:

•  Hard to independently validate •  Weighting for each criterion?

•  ARV-ARV interactions not considered •  No accounting for the effect of an impaired BBB •  Anatomy: CSF not “a liquid brain biopsy” •  Efficacy in brain cells not assessed specifically •  Toxicity (CNS/CVS) not considered

Slide from Dr Anton Pozniak; Consultant Physician, C&W.

HIVCogni<veImpairment:cART-era

•  RandomisedcontroltrialhighCPEvslowCPE–  No neuropsychological benefit at 16 weeks

–  Higher detectable plasma HIV viral load in high CPE group (i.e. treatment failure)

Ellis RJ, Letendre S, Vaida F, Haubrich R, Heaton RK, Sacktor N, Clifford DB, Best BM, May S, Umlauf A, Cherner M, Sanders C, Ballard C, Simpson DM, Jay C, McCutchan JA. Randomized Trial of Central Nervous System-Targeted Antiretrovirals for HIV-Associated Neurocognitive Disorder. Clin Infect Dis. 2014 Jan 14.

HIVCogni<veImpairment:Toxicity

•  ACTG5170Mul<centrestudyofdiscon<nua<onofARVsinthosewithCD4>350

•  MixtureofARVs

Robertson, K.R., et al. Neurocognitive effects of treatment interruption in stable HIV-positive patients in an observational cohort. Neurology 74, 1260-1266 (2010).

Winston, A., et al. Dynamics of cognitive change in HIV-infected individuals commencing three different initial antiretroviral regimens: a randomized, controlled study. HIV Med (2011). EFAVIRENZ

An Approach to Assessment & Treatment of Cognitive Impairment in ART-treated HIV patients.

From: Davies & Brew (2014) Clinical Aspects of HIV-Related Neurocognitive Disorders In: HIV & Psychiatry, Editors: Joska, Stein & Grant. DOI: 10.1002/9781118339503.ch3

HIVCogni<veImpairment:cART-era

•  Whatwillbetheeffectoflong-termARVexposuretotheCNS?– Mitochondria;proteosomes

•  Whatwillbetheeffectofvasculardysfunc<on?•  Whatwillbetheeffectofdyslipidaemia?